The Mystery of Vobarilizumab (ALX-0061) 2nd Part

If you look for vobarilizumab at the ACR, the last publication has been at the 2014 meeting [1]. The conclusion had been: “ALX-0061 demonstrates in vitro a preferential binding profile for sIL-6R with a lesser activity for mIL-6R, while TCZ has a higher preference for mIL-6R. Preferential inhibition of sIL-6R trans-signalling by ALX-0061 could provide improved therapeutic efficacy with a better safety profile compared to TCZ.”

In 2016 AbbVie opted not to license vobarilizumab, but Ablynx wanted to seek a new partner for further development [2].

In March 2018 Ablynx announced that vobarilizumab did not meet the primary endpoint of dose response in a phase 2 study on systemic lupus erythematodes at week 24 [3]. IL-6 “induces terminal differentiation of B lymphocytes into antibody-forming cells and the differentiation of T cells into effector cells” [4] Pfizer discontinued a phase 2 study of PF-4236921 (an IL-6 inhibitor) for systemic lupus erythematosus in October 2015 [5]. But still stranger to me is the fact that tocilizumab hasn’t opted for an approval for lupus. As a matter of fact, if you search PubMed for tocilizumab in systemic lupus you’ll find about 20 studies, but none showing a move towards SLE as an indicated disease [6]. I once exploited the chance to talk to Professor Kishimoto (岸本忠三), who developed anti-IL-6 receptor therapy, but tocilizumab in SLE wasn't one of our topics. Still Ablynx tries to ride a dead horse.

I don’t see much room for vobarilizumab. I also don’t see any phase 3 study (RA) on the horizon. But let’s wait if motivation and conviction reappear as well as a sponsor for the needed phase 3 study shows up.

Links:

[1] Abstract Number: 1498; Maarten Van Roy and collaegues: ALX-0061, an Anti-IL-6R Nanobody® for use in Rheumatoid Arthritis, Demonstrates a Different in Vitro Profile As Compared to Tocilizumab - http://acrabstracts.org/abstract/alx-0061-an-anti-il-6r-nanobody-for-use-in-rheumatoid-arthritis-demonstrates-a-different-in-vitro-profile-as-compared-to-tocilizumab/

[2] https://www.genengnews.com/gen-news-highlights/abbvie-opts-against-licensing-ablynxs-vobarilizumab/81253340

[3] https://globenewswire.com/news-release/2018/03/26/1452561/0/en/ABLYNX-ANNOUNCES-TOPLINE-RESULTS-FROM-THE-PHASE-II-STUDY-OF-VOBARILIZUMAB-IN-PATIENTS-WITH-SYSTEMIC-LUPUS-ERYTHEMATOSUS.html

[4] https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2014821/

[5] https://adisinsight.springer.com/drugs/800029000

[6] Search in PubMed: "tocilizumab" [Supplementary Concept]) AND "Lupus Erythematosus, Systemic"[Mesh] https://www.ncbi.nlm.nih.gov/pubmed/?term=%22tocilizumab%22+[Supplementary+Concept]%29+AND+%22Lupus+Erythematosus%2C+Systemic%22[Mesh]

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Vobarilizumab (ALX-0061) at the 2017 ACR Annual Meeting in San Diego

As vobarilizumab has caught my interest a while ago [1], I had already looked closer at this anti-IL6 receptor (IL-6R) nanobody® at the 2017 EULAR Annual Meeting in Madrid [2] and concluded: “The data is interesting and promising, but the big question remains: will there be a phase 3 study?”

There had been one study on vobarilizumab at the 2017 ACR Annual Meeting in San Diego, just one.

M. Rinaldi and colleagues presented [3]: “Assessment of Dose Dependent Effects of Vobarilizumab, an Anti-IL6 Receptor (IL-6R) Nanobody®, on Systemic Biomarkers in Patients with Moderate-to-Severe Rheumatoid Arthritis (RA): Results of Two Phase 2b Studies”. The authors looked at the effect of vobarilizumab and tocilizumab on biomarkers like CRP, ESR, soluble IL-6 receptor (sIL-6R), matrix metalloproteinase-3, and chemokine ligand 13 (CXCL13). The authors concluded: “The observed dose dependent PD [pharmacodynamics] biomarker responses and effects on cartilage degradation and joint inflammation biomarkers further support the strong potential for disease modifying activity of vobarilizumab in RA [rheumatoid arthritis].”

A bit disappointing, isn’t it? Not the results, but the slowing down of research and commitment. I’ve just looked, if there is a phase 3 study [4], but didn’t find one. Abbvie seems to kindle a fire so light, that it might be blown out soon.

Links and References:

[1] http://rheumatologe.blogspot.de/2016/11/the-mystery-of-vobarilizumab-alx-0061.html

[2] http://rheumatologe.blogspot.de/2017/06/vobarilizumab-alx-0061-at-2017-eular.html

[3] Rinaldi M, Van Bogaert T, Van Roy M, Bontinck L, Hohlbaum A, Snoeck V, Dombrecht E, Van Beneden K, Schoen P, Ulrichts H. Assessment of Dose Dependent Effects of Vobarilizumab, an Anti-IL6 Receptor (IL-6R) Nanobody®, on Systemic Biomarkers in Patients with Moderate-to-Severe Rheumatoid Arthritis (RA): Results of Two Phase 2b Studies [abstract]. Arthritis Rheumatol. 2017; 69 (suppl 10). http://acrabstracts.org/abstract/assessment-of-dose-dependent-effects-of-vobarilizumab-an-anti-il6-receptor-il-6r-nanobody-on-systemic-biomarkers-in-patients-with-moderate-to-severe-rheumatoid-arthritis-ra-results-of-two/ .Accessed January 13, 2018.

[4] https://clinicaltrials.gov/ct2/results?cond=&term=ALX-0061&cntry=&state=&city=&dist=&Search=Search

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Biosimilars und Biologika auf dem DGRh Kongress 2017 in Stuttgart

Warum ist die Politik so daran interessiert, warum Krankenkassen, Patientenverbände, Fachgesellschaften? Weil sie zuvor ihre Hausaufgaben nicht gemacht haben. Denn sie haben der Preisexplosion nicht Einhalt geboten. Das fing schon vor den Biologika an, aber hierbei ist es doch besonders offensichtlich – und ein Ende ist da nicht in Sicht, wenn wir an die small molecules wie Tofacitinib oder Baricitinib denken. So steigen die Preise weiter an. Der Markt wird immer unüberschaubarer.

Biosimilars kommen wie Innovationen daher, als hätte die Welt darauf gewartet, aber es sind schließlich nur  Imitate; die entscheidenden Ideen haben andere gehabt und in Studien die Wirksamkeit nachgewiesen. Die  Patienten jedenfalls werden damit überfordert. Insbesondere wo es neben Biosimilars auch schon Bioidenticals gibt. Auch wenn ich nicht auf Biosimilars gewartet habe, werde ich sie denooch anwenden, besser anwenden müssen.

Welche Biosimilars haben wir denn? Welche Biologika wurden denn vorgestellt? Gab es funkelnagelneue Bio***s? In dieser Übersicht werde ich mich auf den Einsatz dieser Medikamentengruppe in der Therapie der rheumatoiden Arthritis, der Psoriasisarthritis und den seronegatiben Spondyloarthritiden beschränken.

Biosimilar-Kandidaten zu Humira® (Adalimumab) BI 695501 von Boehringer Ingelheim - ENCORE.42 (Encore sind Poster, die bereits anderswo gezeigt wurden) - das Poster beschäftigt sich mit dem Autoinjektor. Encore.47 beschäftigt sich mit Wirksamkeit und Nebenwirkung und findet keinen wesentlichen Unterschied.

Ansonsten fanden sich viele Poster zu Secukinumab, aber auch Daten zu Tocilizumab, Certolizumab, Canakinumab, Sarilumab, Abatacept, Golimumab, Rituximab, Ixekizumab und Infliximab.

H. Kellner präsentierte Daten aus seiner Schwerpunktpraxis (EV.13): " Hohe Patientenakzeptanz bei Neueinstellung oder Umstellung von Originalabiologika (Enbrel, Remicade) auf Biosimilar-TNF Ak". Die Arbeit hat nur geringe Fallzahlen. In der Schlussfolgerung lesen wir: "Den angesprochenen Patienten ist die Möglichkeit einer substanziellen Kostenersparnis bei Einsatz von Biosimilar durchaus bewußt und ein wesentliches Element der Bereitschaft selbst Biosimilars zu verwenden." Das kann ich so aus den Ergebnissen nicht herauslesen. Ob eine Kostenersparnis dauerhaft gegenüber den Originalherstellern bestehen bleibt, muss die Zukunft zeigen, denn es wird wahrscheinlich zu Festpreisen kommen.

Zusammenfassend spielen die Biosimilars in der Wissenschaft eine untergeordnete Rolle. Das liegt in der Natur der gesetzlichen Bestimmungen, denn es muss nur der Nachweis von gleicher Effektivität und Nebenwirkung zum Orinalpräparat in einer Indikation nachgewiesen werden. Das sollte auch leicht möglich sein, wenn die Strukturgleichheit gegeben ist - und davon ist auszugehen. Für Infliximab haben wir die Biosimilars Remsima®, Inflectra® und Flixabi®, wovon Remsima® und Inflectra® bioidentisch sind, d.h. sie haben einen Hersteller und zwei Vertreiber. Für Etanercept haben wir die Biosimilars Benepali® und Erelzi™. Für Rituximab ist das Biosimilar Truxima® zugelassen. Für Adalimumab ist das Biosimilar Amjevita™ in den USA zugelassen und wird neben anderen hier in der nahen Zulunft erwartet [1].

Für die o.g. Originalpräparate ist eine Fülle von neuen Daten veröffentlicht worden. Allerdings habe ich nichts zu Mavrilimumab und Vobarilizumab gefunden.

Links:

[1] http://rheumatologe.blogspot.de/2016/12/possible-problems-with-piosimilars.html

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Vobarilizumab (ALX-0061) at the 2017 EULAR Annual Meeting in Madrid

I’ve written about the “The Mystery of Vobarilizumab (ALX-0061)” on this blog [1] and asked the question: “will the phase 3 study really start? And when it starts, will vobarilizumab show a significant reduction in radiographic progression.”

Clinical Trial lists six studies for Vobarilizumab (ALX-0061) [2], one recruiting, another one still active, the others completed.

“Vobarilizumab is a Nanobody® consisting of an anti-IL-6R domain and an anti-human serum albumin domain in development for treatment of RA.” At the 2017 EULAR Annual Meeting Vobarilizumab has been discussed in two studies.

T. Dörner and colleagues presented the following study [3]: “REMISSION AND MAINTENANCE OF EFFICACY IN A PHASE 2B STUDY OF VOBARILIZUMAB, AN ANTI-INTERLEUKIN 6 RECEPTOR NANOBODY, IN PATIENTS WITH MODERATE-TO-SEVERE RHEUMATOID ARTHRITIS DESPITE TREATMENT WITH METHOTREXATE”. The authors concluded: “In patients with active RA, treatment with vobarilizumab at the 3 highest dose regimens in addition to MTX had a positive and sustained impact on disease activity through Week 24 as defined by clinically relevant efficacy endpoints.”

And T. Dörner and colleagues presented a second study [4]: “RESULTS OF A PHASE 2B STUDY OF VOBARILIZUMAB, AN ANTI-INTERLEUKIN-6 RECEPTOR NANOBODY, AS MONOTHERAPY IN PATIENTS WITH MODERATE TO SEVERE RHEUMATOID ARTHRITIS”. In this study the conclusions are: “In patients with active RA, treatment with vobarilizumab monotherapy had a positive impact on disease activity with no unexpected safety findings.” Tested against tocilizumab, vobarilizumab fared well. The data puts tocilizumab at 162mg q1w in between vobarilizumab at 150mg q2w and 225mg q2w.

The data is interesting and promising, but the big question remains: will there be a phase 3 study? Ablynx didn’t mention a phase 3 study up until today [4].

Links and References:

[1] http://rheumatologe.blogspot.de/2016/11/the-mystery-of-vobarilizumab-alx-0061.html

[2] https://clinicaltrials.gov/ct2/results?term=ALX-0061&Search=Search

[3] Annals of the Rheumatic Diseases, volume 76, supplement 2, year 2017, page 92 / Session: Progress in biological treatment of RA , (Oral Presentations ) / DOI: 10.1136/annrheumdis-2017-eular.3732

[4] http://www.ablynx.com/rd-portfolio/clinical-programmes/vobarilizumab/

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